Maternal Diabetes as an Independent Risk Factor for Retinopathy of Prematurity in Infants With Birth Weight of 1500 g or More




Purpose


To evaluate the relationship between maternal diabetes and the development of retinopathy of prematurity (ROP) in infants with a birth weight of 1500 g or more.


Design


Retrospective case-control study.


Methods


Data of 78 premature infants from diabetic mothers were compared with data of 258 controls. We examined the relationship between maternal diabetes and the development of ROP and type 1 ROP, adjusting for multiple risk factors. Multivariable logistic regression analysis was used to identify the risk factors of outcome variables. Prior to multivariable logistic regression analysis, the association of each independent variable with the outcome variables, a univariate estimate was performed. The crude and adjusted odds ratio (OR) values and their 95% confidence intervals (CI) were given. Main outcome measures were the development of ROP and the development of type 1 ROP.


Results


The study was conducted on 336 preterm infants; 78 were from diabetic mothers and 258 were from nondiabetic mothers. The rate of ROP (78.2% in case group and 14.7% in control group) and the rate of type 1 ROP (20.5% in case group and 4.7% for controls) were found significantly higher in the case group ( P = .001 for both). Maternal diabetes was shown to be an independent risk factor for both ROP and type 1 ROP (OR with 95% CI: 25.040 [12.728–49.264]; 6.311 [2.647–15.048], respectively, and P < .001 for both).


Conclusion


Our data suggest that the presence of maternal diabetes is significantly associated with the development of ROP and type 1 ROP in premature infants with a birth weight of 1500 g or more.


Retinopathy of prematurity (ROP) is the source of substantial morbidity for premature babies all over the world. Affected babies from developing countries have a wider range of birthweight (BW) and gestational age (GA) compared with those from developed countries. According to the published ROP screening guidelines, it is recommended that all premature infants with BW of 1500 g or less be screened. But guidelines are not so clear for babies with BW over 1500 g, and ROP screening is advised for infants who are supposed to be at high risk for ROP.


ROP and diabetic retinopathy are both retinal vascular diseases, in which there is leakage and/or neovascularization from damaged retinal vessels on the basis of retinal ischemia. In intrauterine life, the human fetus is nearly completely dependent on maternal glucose passing through the placenta by facilitated diffusion. The overall glucose flow traces a maternal-to-fetal concentration gradient up to 360 mg/dL. The negatory outcomes on the fetus and the mother increase linearly with increasing maternal plasma glucose. Maternal hyperglycemia can give rise to fetal hyperglycemia and causes macrosomia, prematurity, and respiratory distress syndrome (RDS). In other words, infants born to diabetic mothers are the babies who are exposed to hyperglycemia in intrauterine life; and despite being larger babies, they may still be significantly premature infants who require oxygen therapy.


Based on all this information, we hypothesized that ROP would be more common in infants born to diabetic mothers, and we aimed to investigate the relationship between maternal diabetes and development of ROP in infants with BW of 1500 g or more.


Methods


We executed a retrospective case-control study examining the relationship between maternal diabetes and development of ROP, adjusting for multiple risk factors. The study was approved by the hospital ethics committee (Zekai Tahir Burak Education and Research Hospital Ethics Committee; registration number: 31.07.15-36.) and informed written consent was obtained from the parents or guardians before enrollment. All work was conducted in accordance with the Declaration of Helsinki and with the approval of the Institutional Review Board.


Data Collection


We reviewed the records of infants born during the period January 1, 2010 through December 31, 2014 who were screened for retinopathy of prematurity. Infants with BW of 1500 g or more and who were referred for ROP examination by their attending neonatologist or pediatrician were included in the study. All the babies in the case and control groups were followed according to the same criteria. The criteria for ROP screening for the babies over 1500 g of BW were sepsis and/or requirement of cardiorespiratory support. Infants from diabetic mothers were defined as the case group. Controls were matched 4:1 with cases for GA and year of birth. Neonates with congenital or chromosomal anomalies or major ocular abnormalities in 1 or both eyes and those who died or were lost to follow-up were excluded.


Recommendations of the American Academy of Ophthalmology, the American Academy of Pediatrics, and the American Association for Pediatric Ophthalmology and Strabismus were followed for ROP examination and screening schedule. The examinations were performed using an eyelid speculum, scleral depressor, binocular indirect ophthalmoscope, and 20 diopter lens after pupillary dilation. The “International Classification of ROP Revisited” was used to classify, diagram, and record the retinal findings at the time of examination. Treatment algorithms were based on the recommendations of the “Early Treatment for ROP” and the infants with type 1 ROP were treated with diode laser photocoagulation.


Demographic information and risk factors including BW, GA, singleton or multiple gestations, oxygen therapy with continuous positive airway pressure (CPAP), mechanical ventilation (MV), RDS, hemodynamically significant patent ductus arteriosus (PDA), culture-proven sepsis, necrotizing enterocolitis (NEC, ≥stage 2), intraventricular hemorrhage (IVH, ≥grade 2), bronchopulmonary dysplasia, neonatal glucose irregularity (blood glucose >180 mg/dL and/or <40 mg/dL), assisted reproduction, pre-eclampsia, and maternal diabetes were extracted from the infant’s medical records. Target range of oxygen saturation in our neonatal intensive care unit (NICU) was 85%–94% during the study period.


Maternal diabetes mellitus was recorded as gestational (GDM) or pregestational; however, the results (the rate of ROP and the rate of type 1 ROP) were similar with pregestational (n = 7) and gestational (n = 71) diabetic mothers, and their data were pooled for analyses. The method for diagnosis of gestational diabetes is a glucose challenge test (50 g) as a screening test followed by a complete oral glucose tolerance test (OGTT) (100 g) in case of abnormal screen. Cutoff level for 50 g glucose challenge test was 140 mg/dL. Cutoff levels for 100 g OGTT test were 95 mg/dL for fasting blood glucose, 180 mg/dL for 1 hour, 155 mg/dL for 2 hours, and 140 mg/dL for 3 hours after OGTT. GDM was diagnosed if 2 plasma glucose levels were detected above the cutoff value. Screens were universally performed between 24 and 28 weeks of gestation.


Power Analysis


The sample size needed for the study was computed based on the primary dependent variable of the development of ROP with the binary independent variable of maternal diabetes. The R 2 was assumed as 0.50 when the maternal diabetes was regressed on other independent variables; odds ratio was chosen as 20 (under the assumption that the probability of ROP is 0.70 for maternal diabetes [+] infants and 0.10 for maternal diabetes [−] infants according to our pilot study). With these specifications, a sample size of 336 observations achieves 96% power at a 0.05 significance level. Power analysis was done via G*Power 3.


Statistical Analysis


Statistical analyses were performed using SPSS version 16.0 (SPSS Inc, Chicago, Illinois, USA). Frequency (percent) for categorical variables and mean ± standard deviation for metric variables were given as descriptive statistics. The χ 2 test was used to compare 2 independent groups for categorical variables, and Student t test was used for metric variables. Phi correlation coefficient was used to assess the degree of association between categorical variables. In order to identify risk factors of outcome variables (the development of ROP and for the development of type 1 ROP), multivariable logistic regression analysis was used. Prior to multivariable logistic regression analysis, the association of each independent variable with the outcome variables, a univariate estimate was performed. The crude and adjusted odds ratio (OR) values and their 95% confidence interval (CI) were given. Although the entry and removal criteria (in terms of P values) were .05 and .10 in multivariable logistic regression analysis, P < .05 was considered as statistically significant in univariate analyses.




Results


A total of 340 infants (79 babies in the case group and 261 in the control group) with a BW of 1500 g or more were reviewed during the study period. Four infants were excluded because of insufficient follow-up (1 infant in the case group and 3 in the control group); thus, the study was conducted on 336 infants. A total of 78 charts of infants who were born to mothers with diabetes mellitus were analyzed in the case group. The infants in the case group were matched with 258 controls (who were not born to mothers with diabetes) for GA (28–36 weeks, mean 32.1 weeks) and birth year. The BW, the rate of ROP, and the rate of type 1 ROP were found to be significantly higher in the case group ( Table 1 ).



Table 1

Comparison of Gestational Age, Birthweight, Rate of Retinopathy of Prematurity, and Rate of Type 1 Retinopathy of Prematurity Between Case and Control Groups





























Case Group (n = 78) Control Group (n = 258) P
Gestational age (wk) (mean ± SD) 32.1 ± 1.9 32.1 ± 1.8 .695 a
Birthweight (g) (mean ± SD) 1852 ± 294 1735 ± 176 .001 a
Retinopathy of prematurity (%) 78.2% 14.7% .001 b
Type 1 retinopathy of prematurity (%) 20.5% 4.7% .001 b

a Student t test.


b χ 2 test.



For the glucose challenge test (50 g), the mean plasma glucose level was found to be 182 mg/dL (160–221 mg/dL) for the mothers of infants in the case group. For the OGTT test (100 g), the mean plasma glucose levels were determined to be 103 mg/dL, 186 mg/dL, 148 mg/dL, and 144 mg/dL for fasting, 1 hour, 2 hours, and 3 hours, respectively. Of the 78 diabetic mothers in the case group, 69 (88.5%) were treated with lifestyle modification and dietary regulation and 9 (11.5%) were treated with insulin. The mean GAs for glucose challenge test and for OGTT were 26.2 weeks and 27.5 weeks, respectively.


Results from simple logistic regression analysis of maternal diabetes, other clinical characteristics, and ROP are shown in Table 2 . ROP was significantly common in infants from diabetic mothers. The other significant clinical characteristics for ROP were neonatal glucose irregularity, sepsis, RDS, and MV. As a result of co-linearity between maternal diabetes and neonatal glucose irregularity (correlation coefficient 0.719, P < .001), as well as between RDS and MV (correlation coefficient 0.457, P < .001), we included only maternal diabetes and MV into the further multivariate analysis model.



Table 2

Association Between Maternal Diabetes, Other Clinical Characteristics, and Retinopathy of Prematurity (Simple Logistic Regression Analysis)













































































































ROP (%) P Crude Odds Ratio [95% CI]
Maternal diabetes
+ 78.2 <.001 20.774 [10.972–39.333]
14.7
Neonatal glucose irregularity
+ 79.6 <.001 15.776 [7.648–32.540]
19.9
Sepsis
+ 51.4 .002 2.926 [1.462–5.858]
26.5
Respiratory distress syndrome
+ 36.6 .003 2.076 [1.278–3.370]
21.7
Mechanical ventilation
+ 37.9 .025 1.757 [1.071–2.882]
25.8
Continuous positive airway pressure
+ 30.5 .542 1.174 [0.701–1.967]
27.2
Patent ductus arteriosus
+ 36.4 .220 1.461 [0.796–2.683]
28.1
Preeclampsia
+ 27.1 .691 .880 [0.469–1.652]
29.7
Necrotizing enterocolitis
+ 50.0 .128 2.527 [0.862–7.408]
28.3
Intraventricular hemorrhage
+ 34.7 .154 1.439 [0.872–2.376]
26.9

+ = present; − = absent.

CI = confidence interval; ROP = retinopathy of prematurity.


Maternal diabetes and sepsis were shown to be independent risk factors for ROP ( Table 3 ). Presence of maternal diabetes was associated with 25 times increased risk of ROP and presence of culture-proven sepsis was related with 3.5 times increased risk of ROP ( Table 3 ).



Table 3

Multivariate Analysis for Retinopathy of Prematurity (Independent Risk Factors for Retinopathy of Prematurity)




















Adjusted Odds Ratio [95% CI] P
Maternal diabetes 25.040 [12.728–49.264] <.001
Sepsis 3.487 [1.473–8.257] .005
Mechanical ventilation 1.860 [0.968–3.576] .063

CI = confidence interval.


Data from simple logistic regression analysis of maternal diabetes, other clinical characteristics, and type 1 ROP is demonstrated in Table 4 . The significant clinical characteristics for type 1 ROP were maternal diabetes, neonatal glucose irregularity, sepsis, RDS, and MV. We found co-linearity again between maternal diabetes and neonatal glucose irregularity, as well as between RDS and MV; we included only maternal diabetes and MV into further multivariate analysis model for type 1 ROP.



Table 4

Association Between Clinical Characteristics and Type 1 Retinopathy of Prematurity













































































































ROP (%) P Crude Odds Ratio [95% CI]
Maternal diabetes
+ 20.5 <.001 5.290 [2.380–11.758]
4.7
Neonatal glucose irregularity
+ 22.2 <.001 4.750 [2.100–10.744]
5.7
Sepsis
+ 24.3 .001 5.000 [2.054–12.169]
6.0
Respiratory distress syndrome
+ 12.0 .011 3.000 [1.239–7.262]
4.3
Mechanical ventilation
+ 17.5 <.001 4.722 [2.096–10.641]
4.3
Continuous positive airway pressure
+ 8.6 .803 1.115 [0.474–2.621]
7.8
Patent ductus arteriosus
+ 9.1 .791 1.122 [0.407–3.090]
8.2
Preeclampsia
+ 6.8 1.000 0.800 [0.266–2.406]
8.3
Necrotizing enterocolitis
+ 21.4 .093 3.375 [0.881–12.923]
7.5
Intraventricular hemorrhage
+ 11.9 .091 1.969 [0.886–4.373]
6.4

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Jan 6, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Maternal Diabetes as an Independent Risk Factor for Retinopathy of Prematurity in Infants With Birth Weight of 1500 g or More

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